T-lymphocytes play a major role in the regulation of B-cell differentiation. These immunoregulatory functions are effected by distinct T-cell subsets. Adenosine can rapidly modulate the immunoregulatory function of human T-lymphocytes and alter the expression of surface antigens and receptors. Adenosine induces development of suppressor activity within a subset of "T-helper/inducer cells." This research project will investigate the cellular mechanisms and the mechanisms of altered surface antigen and receptor expression and the biochemical mechanisms operative in adenosine-induced immunosuppression. The identity of the adenosine responsive cell, its time of action, and cellular target will be investigated. Fractionated T-lymphocyte subsets and adenosine responsive T-cell hybridomas will be used. The mechanisms of adenosine-induced, surface marker alteration will be investigated using selective radioactive labeling techniques to tag surface membrane, intramembrane, and cytosolic proteins. Alterations in the physical characteristics and membrane distribution of these structures caused by adenosine will be investigated using immunoprecipitation followed by analysis with two-dimensional electrophoresis. Adenosine was found to increase phospholipid methylation and arachidonic acid release. The role of phospholipid and arachidonic acid metabolism will be investigated by identifying alterations in phospholipid metabolism in T-lymphocytes caused by adenosine. The immunosuppressive activity of phospholipids will be investigated. The effects of selective inhibitors of arachidonic acid metabolism upon adenosine-induced immunosuppression will be studied to determine which pathways may be important in this process. Adenosine is released from hypoxic and ischemic tissues as well as from aggregating platelets. In\this regard, adenosine may represent a tissue injury signal. The induction of suppressor cells which impair antibody synthesis to autologous injured tissues may be an important immunohomeostatic mechanism to limit autoantibody production. Since adenosine rapidly modifies T-lymphocyte cyclic nucleotide, phospholipid, and arachidonic acid metabolism, this system provides an opportunity to study the relationship between these events and should provide insights into the biochemical basis of immunoregulation. (LB)